Landmark Omagari study first shows CETP-deficiency-driven high HDL cholesterol is not a longevity syndrome (Arterioscler Thromb Vasc Biol 1997)

Low levels of HDL cholesterol have been clearly demonstrated to be associated with an increased incidence of coronary heart disease, strongly suggesting that HDL particles have an antiatherogenic function. However, little information has been available concerning the atherogenicity of a marked hyperalphalipoproteinemia (HALP). There is no agreement about whether plasma cholesteryl ester transfer protein (CETP) deficiency is associated with an antiatherogenic state or not, although this disorder was reported to be one of the major causes of marked HALP. In the current study, we have found a unique area (Omagari City, Akita Prefecture, Japan) where CETP deficiency caused by a G-to-A mutation at the 5' splice donor site of intron 14 in the CETP gene is extremely frequent. In Omagari City, the mutation was detected more than 20 times more frequently and the prevalence of a marked HALP with plasma HDL cholesterol > or = 2.58 mmol/L (100 mg/dL) was 5 to 10 times higher than in other areas of Japan. This discovery has made it possible to perform a large population-based study concerning the atherogenicity of a marked elevation of HDL cholesterol in a genetically more homogeneous population. There was a statistically significant U-shaped relationship between HDL cholesterol levels and the incidence of ischemic changes in electrocardiograms. In cases of HDL cholesterol < 1.81 mmol/L (70 mg/dL), the incidence increased in proportion to the levels of HDL cholesterol. The frequency of the CETP gene mutation was higher in patients with coronary heart disease than in healthy control subjects. In subjects aged > 80 years, the prevalence of both marked HALP and the intron 14 splicing defect was significantly lower than in the younger generation. The current study indicated for the first time that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome, suggesting the importance of reevaluation of the clinical significance and pathophysiology of a marked HALP.